Oral squamous cell carcinoma (OSCC), which accounts for the majority of head and neck cancers. Treatment for OSCC frequently involves a combination of surgery, radiotherapy, and chemotherapy. However, resistance to therapy complicates treatment, and the 5-year survival rate remains at ~65 percent. Understanding contributors to disease progression and treatment resistance is needed to promote patient outcomes. We propose here to study a potential molecular regulator of OSCC. Lysine-specific demethylase 1 (LSD1) is an amine oxidase with demethylase activity and has been implicated in maintaining the undifferentiated state of cancer-initiating cells. Our preliminary studies showed that LSD1 knockdown in HSC- 3 implanted orthotopic tumors attenuates tumor growth and metastasis in mouse models, whereas overexpression of LSD1 promotes it. Small molecule inhibitors (e.g., GSK-LSD1) of LSD1 attenuate disease in patient-derived xenografts (PDXs), EGFR-induced signaling, and pro-oncogenic gene (MMP13, LOXL4 and PD-L1). Microarrays followed by gene set enrichment analysis also showed that GSK-LSD1 inhibits the key mediators of EGFR signaling pathways. We hypothesize that conditional epithelial cell-specific deletion of LSD1 in the oral cavity attenuates epithelial OSCC progression and metastasis by reducing EGFR induced oncogenic signaling network to promote specific target genes. Further, we postulate that GSK-LSD1 in combination with immunotherapy or chemotherapy completely attenuates OSCC. The specific aims of the study are to 1) determine if endogenous LSD1 is a key activator of specific target genes in murine 4NQO OSCC mouse model, and 2) determine if GSK-LSD1 sensitizes OSCC to chemotherapy or immunotherapy in PDOX and 4NQO mouse models by inhibiting EGFR, c-Myc, and PD-L1 signaling pathways. In vitro, ex-vivo, and in vivo approaches as well as microarrays and next- generation sequencing will be employed to address the proposed aims. LSD1 inhibitors could prove useful for OSCC immunotherapy and in personalized combination therapies. Thus, this study has a strong translational potential to identify LSD1 as a novel druggable target and its potential for anti-OSCC monotherapy and combination therapies.